OP0263 FAVORABLE BALANCE OF BENEFIT AND HARM OF LONG-TERM, LOW-DOSE PREDNISOLONE ADDED TO STANDARD TREATMENT IN RHEUMATOID ARTHRITIS PATIENTS AGED 65+: THE PRAGMATIC, MULTICENTER, PLACEBO- CONTROLLED GLORIA TRIAL
Authors: M. Boers, L. Hartman, D. Opris-Belinski, R. Bos, M. R. Kok, J. A. P. da Silva, E. N. Griep, R. Klaasen, C. Allaart, P. Baudoin, H. Raterman, Z. Szekanecz, F. Buttgereit, P. Masaryk, T. Klausch, S. Paolino, A. M. Schilder, W. Lems, M. Cutolo
Journal: Annals of the Rheumatic Diseases (2022)

Background Low-dose glucocorticoid (GC) therapy is widely used in RA but the true balance of benefit and harm is still unknown. Objectives We studied the effects of prednisolone (5 mg/day, 2 years) in RA patients aged 65+, requiring adjustment of antirheumatic therapy (DAS28≥2.60). Methods Pragmatic double-blind placebo-controlled randomized trial; all co-treatments and changes therein were allowed during the trial except long-term open label GC; Ca/D supplementation was advised in all patients. Minimal exclusion criteria were tailored to seniors. Harm outcome: the number of patients with ≥1 serious adverse event (SAE), or ≥1 ‘other adverse event of special interest’ (other AESI). Other AESI comprised any AE (except worsening of RA) causing study discontinuation, and GC-specific events (Table 1). Table 1. Adverse events of special interest (AESI).* prednisolone (n=224) placebo (n=225) Events by protocol-defined category SAE other AESI SAE other AESI Infection 26 124 16 91 Urinary tract 4 49 4 29 Pneumonia 2 17 2 13 Other 20 58 10 49 Cardiovascular 8 2 6 0 Symptomatic fracture 2 11 4 6 New onset Hypertension 1 4 0 7 Diabetes mellitus 0 2 0 1 Cataract 0 7 2 6 Glaucoma 0 1 0 3 Other † 43 43 35 26 Total 80 194 63 140 *AESI: Comprises serious adverse events (SAE) and other AESI, defined by protocol. †‘Other’ other AESI: non-serious AE outside of the above predefined categories, but associated with premature discontinuation. Benefit outcomes: improvement in disease activity (DAS28) and joint damage progression (Sharp/van der Heijde). Longitudinal mixed models analyzed the data. Given prior knowledge we report one-sided 95% confidence limit (95%CL) and statistical tests, performed only for the main outcomes. Results We randomized 451 RA patients in 7 EU countries, 449 received the intervention; of these 63% prednisolone vs 61% placebo patients completed 2 years of follow up. Discontinuations were similar in both groups: for AE (14%) and active disease (4%); the remainder mostly for ‘trial fatigue’ and covid-related access issues (20%). Mean time on study drug was 19 (SD 8) months. 70% of patients were female, mean age was 72 (max 88) years, RA duration 11 years; 67% were RF+, 56% ACPA+, 96% had joint damage on radiographs: mean score 20, median 8. Mean DAS28 was 4.5. Most patients (79%) were on current DMARD treatment, including 14% on biologics; 47% had previously used GC, 14% changed DMARD therapy at baseline. Patients had mean 2.1 active comorbidities, and used median 7 drugs. Benefit: Disease activity rapidly declined to stabilize after 1 year (Figure 1), and was lower on prednisolone (adjusted mean difference in DAS28 over 2 years: 0.37, 95%CL 0.23, p&lt;0.0001). The contrast in early (3-month) response was larger in 331 patients adherent to protocol on stable treatment: mean difference in DAS28 0.62 (95%CL 0.44), more responders on prednisolone (Figure 1). Significant time-treatment interaction in secondary analyses suggested a decrease in contrast after the first year, most likely caused by significantly more changes in DMARD treatment on placebo. Joint damage progression over 2 years was significantly lower on prednisolone: mean 0.6 (SD 1.9) v 1.8 (6.4) score points on placebo, difference 1.2 (95%CL 0.2, p=0.02). Harm: 60% prednisolone vs 49% placebo patients experienced the harm outcome: adjusted RR 1.24, 95%CL 1.04, p=0.02; number needed to harm 9.5 (Table 1). During the study 1 vs 2 patients died, and 3 vs 0 died within 5 months of discontinuation. Per 100 patient-years, AE totaled 278 in prednisolone vs 206 in placebo patients, and the difference was most marked for infections (Table 1); these were mostly mild or moderately severe. Other GC-specific AESI were rare without relevant differences. Conclusion Add-on low dose prednisolone has beneficial long-term effects on disease activity and damage progression in senior RA patients on standard treatment. The tradeoff is a 24% increase in patients with mostly mild to moderate AE, suggesting a favorable balance of benefit and harm. Acknowledgements Trial registration: NCT02585258 (clinicaltrials.gov). The trial is part of a larger project funded by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 634886. Apart from the listed authors and centers, the GLORIA Trial Consortium comprises: L.M. Middelink, Middelinc BV The Netherlands, Operational Lead; V. Dekker, Amsterdam UMC, Vrije Universiteit, Financial Lead; Partners: Trial operations: N. van den Bulk, CR2O BV, The Netherlands; Study Medication (Development, Manufacturing &amp; Supply): R.M.A. Pinto, Bluepharma – Indústria Farmacêutica, S.A., Portugal; Data management: L. Doerwald, Linical Netherlands BV, The Netherlands; S. Manger, Department of Epidemiology &amp; Data Science, Amsterdam UMC, Vrije Universiteit, The Netherlands. Adherence monitoring: J. Redol, BeyonDevices LDA, Portugal; Safety monitoring: K. Prinsen, Clinfidence BV, The Netherlands; Patient partner: M. Scholte-Voshaar, Stichting Tools (Tools2Use), The Netherlands. Investigators (other recruiting centers): T.L.T.A. Jansen, VieCuri – location Venlo, The Netherlands; C. Codreanu, Clinical Center for Rheumatic Diseases, Bucarest, Rumania; R.M.Zandhuis-Mooij, MSc, Gelre Ziekenhuis, Apeldoorn, The Netherlands; E. Molenaar, Groene Hart Ziekenhuis, Gouda, The Netherlands; J.M. van Laar, UMC Utrecht, The Netherlands; Y.P.M. Ruiterman, Haga Ziekenhuis, Den Haag, The Netherlands; A.E.R.C.H. Boonen, MUMC, Maastricht, The Netherlands; M. Micaelo, Instituto Português de Reumatologia, Lisboa, Portugal; J. Costa, Hospital de Ponte Lima, Portugal; M. Sieburg, Rheumatologische Facharztpraxis Magdeburg, Germany; J.P.L. Spoorenberg, UMC Groningen, The Netherlands; U. Prothmann, Knappschaftsklinikum Saar GbmH, Puettlingen, Germany; M.J. Saavedra, Hospital de Santa Maria, Lisboa, Portugal; I. Silva, Hospital de Egas Moniz, Lisboa, Portugal; M.T. Nurmohamed, Reade, Amsterdam, The Netherlands; J.W.G. Jacobs, UMC Utrecht, The Netherlands; and S.W. Tas, Amsterdam UMC, University of Amsterdam, The Netherlands. Scientific Advisory Committee: J.W.J. Bijlsma, UMC Utrecht, The Netherlands; R. Christensen, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; Y.M. Smulders, Amsterdam UMC, VU University, The Netherlands; and S.H. Ralston, University of Edinburgh, Edinburgh, UK. Radiographic assessment: D.M.F.M. van der Heijde (Imaging Rheumatology BV, the Netherlands) coordinated the reading of the hand and foot x-rays. A.F. Marsman and W.F. Lems scored the spine X-rays. Patient panel: C. Rusthoven and M. Bakkers, The Netherlands E. Frazão Mateus, and G. Mendes, Portugal C. Elling-Audersch and D. Borucki, Germany A. Cardone, Italy P. Corduta and O. Constantinescu, Romania P. Richards, United Kingdom G. Aanerud, Norway Disclosure of Interests Maarten Boers Consultant of: Novartis, Linda Hartman: None declared, Daniela Opris-Belinski Consultant of: Abbvie, Pfizer, MSD, Novartis, Eli Lilly, Ewo Pharma, UCB, Reinhard Bos: None declared, Marc R Kok: None declared, José Antonio P. da Silva: None declared, Eduard N. Griep: None declared, Ruth Klaasen: None declared, Cornelia Allaart: None declared, Paul Baudoin: None declared, Hennie Raterman Consultant of: Abbvie, Pfizer, MSD, Novartis, Eli Lilly, Ewo Pharma, UCB, Zoltán Szekanecz: None declared, Frank Buttgereit Consultant of: Abbvie, AstraZeneca, Gruenenthal, Horizon Therapeutics, Mundipharma, Pfizer, Roche, Pavol MASARYK: None declared, Thomas Klausch: None declared, Sabrina Paolino: None declared, Annemarie M. Schilder Consultant of: Eli Lilly, Novartis, Genzyme, WIllem Lems Consultant of: Pfizer, Galapagos, Lilly, Amgen, UCB., Maurizio Cutolo: None declared